1. Field of the Invention
The present invention relates to pharmaceutical compositions comprising prostaglandin-related compounds and trefoil factor family peptides.
2. Description of Related Art
Active drugs often have undesirable side effects at their therapeutically effective concentrations. This is particularly problematic for topical use in sensitive areas such as the eyes, where irritation is very difficult to avoid even for relatively mild drugs. As a result, formulating topical ophthalmic drugs is a particularly challenging problem. This is unfortunate because topical ophthalmic use of drugs has been found to be very useful in managing many conditions affecting the eye such as dry eye, infection, inflammation, allergy, and glaucoma. Glaucoma is a particularly devastating disease of the eye characterized by increased intraocular pressure, which is often treated by topical ophthalmic application of a drug. Glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. In cases where surgery is not indicated, many drugs have been found to be useful in treating glaucoma by topical application including β-adrenoreceptor antagonists and α2-adrenoreceptor agonists. Recently, prostaglandins have been shown to be particularly useful in the topical treatment of glaucoma.
Whereas prostaglandins appear to be devoid of significant intraocular side effects, ocular surface (conjunctival) hyperemia, foreign-body sensation, and itching (pruritus) have been consistently associated with the topical ocular use of such compounds, in particular PGF2α and its prodrugs, e.g., its 1-isopropyl ester, in humans. The clinical potentials of prostaglandins in the management of conditions associated with increased ocular pressure, e.g. glaucoma are greatly limited by these side effects.
U.S. Pat. No. 5,688,819, commonly assigned to Allergan, Inc., and incorporated herein by reference discloses compounds known as prostamides. Prostamides are distinguished from prostaglandins in that the oxygen which is bonded to carbonyl group is replaced by a nitrogen bearing substituent. Those skilled in the art will readily recognize that this replacement significantly alters several electronic and steric properties of an important structural feature in the biological molecule. Significantly, it is commonly believed in the art that resonance between the nitrogen lone pair and the carbonyl π-bond is significantly greater than resonance between the carbonyl group and an oxygen lone pair in a carboxylic ester or a carboxylic acid. This belief is supported by the well established experimental observation that the nitrogen atom in an amide is planar, as opposed to the pyramidal geometry of an amine. Thus, the commonly accepted belief in the art is that the nitrogen atom of an amine is sp3 hybridized, while nitrogen atom of an amide is sp2 hybridized, with the bonded electrons occupying the sp2 hybrid orbitals and the nonbonded electron pair occupying a p orbital to allow for conjugation with the carbonyl π system. By contrast, the hybridization, bonding, and geometry of the electrons of the oxygen atom in water and alcohols are very similar to those of carboxylic acids or carboxylic esters.
The increased resonance between the nitrogen and the carbonyl group in the amide confers several unique properties to the molecule. First, it is well known in the art that hydrolysis of amides is at least two orders of magnitude slower than the hydrolysis of esters (see, for example, Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company, 1987, p. 779). Thus, hydrolysis of amides in vivo is slowed to such an extent that a prostamide cannot be considered to be a prodrug of a prostaglandin. Second, the increased resonance significantly increases the barrier to rotation about the nitrogen-carbonyl sigma bond relative to the analogous rotational barrier associated with esters and carboxylic acids. Thus, a prostamide has a sterically significant, stable, rigid group replacing the oxygen atom of the prostaglandin. This significant steric difference will have a significant effect in binding to a number of receptor sites since geometry is important for many receptor sites. Since the carboxylic acid group of a prostaglandin is a polar, ionizable, group, with four potential hydrogen bond receiving electron pairs, and in the case of the protonated acid, one potential hydrogen bond donor, it is reasonable for a person of ordinary skill in the art to believe that this functional group will be important to the binding of the molecule to a number of receptors. It follows that changing the resonance properties, the hybridization of the bonding and nonbonding electrons, the geometry of the nitrogen atom, the number of available hydrogen bonding sites, and the electronegativity of the of the nitrogen relative to oxygen, will confer significantly different biological properties to prostamides relative to prostaglandins.
Recently, it is becoming more commonly accepted in the art that amides have distinct properties over carboxylic acids. For example, it has been shown that anandamide, a common amide of arachidonic acid, has significant biological activity that arachidonic acid does not. Other work has also been done to show that amides have distinct activity as compared to carboxylic acid, which has caused some in the field to classify fatty acid amides as “a new family of biologically active lipids” (Bezuglov, et. al., “Synethesis and Biological Evaluation of Novel Amides of Polyunsaturated Fatty Acids with Dopamine”, Bioorganic & Medicinal Chemistry Letters 11 (2001), 447-449).
It has been shown that prostamides have pronounced effects on smooth muscle and are potent ocular hypotensive agents. Additionally, prostamides cause significantly lower ocular surface hyperemia than prostaglandins. One prostamide exemplary of the these effects is bimatoprost, which is marketed by Allergan, Inc. under the trade name Lumigan®, which has the structure shown in Formula I below.
However, although bimatoprost is associated with significantly less hyperemia and other irritating side effects compared to certain prostaglandins, further improvement is still highly desirable.
Trefoil peptides, or trefoil factor family (TFF) peptides are a class of peptides which comprise a common structural motif, known as the trefoil domain, as part of their structure. The trefoil motif comprises about 20 to about 60 amino acid residues (usually about 40) containing six cysteine residues. The six cysteine residues form three disulfide bridges that complete three loops in the peptide chain so that the roughly 40 residues have a clover-like shape, known as the trefoil domain. TFF-peptides can have one or two trefoil domains per molecule, and may comprise additional amino acid residues which are not part of the trefoil domain. To date, three types of TFF-peptides have been isolated from humans-TFF1 (also known as pS2), TFF2 (also known as SP), and TFF3 (also known as ITF). TFF1 and TFF3 peptides each contain one trefoil domain, while TFF2 peptides contain two trefoil domains. TFF1 and TFF2 peptides are both produced by mucus-producing cells of stomach, while TFF3 peptides are produced by goblet cells of small and large intestine.
All three forms of TFF-peptides are known to be produced in epithelial cells around areas of damage to mucus membrane, suggesting that trefoils have a role in healing injury, particularly to epithelial cells. It is believed that TFF-peptides assist healing by both stabilizing mucus membrane at the injury site and by stimulating repair. It has been shown that TFF-peptides noncovalently link mucin, thus influencing the rheology (e.g. increases viscosity) of mucus gels. [Hauser F, Poulsom R, Chinery R, et al, Proc Natl Acad Sci USA, 1993, vol. 90, pp. 6961-6965; and Babyatsky M W, deBeaumont M, Thim L, Podolky D K, Gastroenterology, 1996, vol. 110, pp. 489-497]. TFF-peptides also appear to be responsible for promoting the migration of epithelial cells to the site of injury, thus stimulating repair. [Göke M, et al, Experimental Cell Research, 2001, vol 264, pp. 337-344; and Playford R J, Journal of the Royal College of Physicians of London, vol 31, pp. 37-40]
Although there is still a great deal unknown about the role of TFF peptides on the ocular surface, in the lacrimal gland, in the efferent passages, and in surrounding tissue, it is believed that TFF-peptides may be present during healing and other related processes in the eye. Biosynthesis and storage TFF1 and TFF3 peptides, but not TFF2,is known to occur in the human conjunctival epithelium [Langer G, et al, Invest Opthalmol Vis Sci, 1999, vol. 40, pp. 2220-2224], and in vitro studies have shown that TFF2 and TFF3 peptides promote the migration of wounded corneal epithelial cells from rabbits [Göke M, et al, Experimental Cell Research, 2001, vol 264, pp. 337-344]. However, to the best of our knowledge, no direct relationship has been unambiguously established between TFF-peptides and any pathological condition affecting the eye.